© National HIV Curriculum PDF created September 25, 2021, 9:00 am Hepatitis B Coinfection This is a PDF version of the following document: Module 4: Co-Occurring Conditions Lesson 5: Hepatitis B Coinfection You can always find the most up to date version of this document at https://www.hiv.uw.edu/go/co-occurring-conditions/hepb-coinfection/core-concept/all. Background Epidemiology Hepatitis B virus (HBV) is a significant cause of liver disease among persons with HIV. For individuals with HIV who were born in the United States, acquisition of HBV occurs primarily through injection drug use and sexual contact, with most HBV infections occurring in adulthood.[1,2] Foreign-born persons, however, are likely to have acquired HBV earlier at birth or in childhood. Genotypes A-H for HBV are geographically distributed, with genotype A as the predominant subtype in the United States among non-Asians and genotype B or C among Asians.[3] In the HIV Outpatient Study (HOPS) during the years 1996 through 2007, investigators reported 8.4% of persons with HIV tested positive for chronic HBV (either HBsAg-positive or HBV DNA positive), a prevalence 20-fold higher than the 0.42% prevalence in the general population (Figure 1).[4] In this same study, they reported the highest rate of chronic HBV was among men who have sex with men (Figure 2).[4] A separate review estimated an overall HBV prevalence of 6 to 14% among individuals with HIV in Western Europe and the United States, with prevalence rates of 4 to 6% in heterosexuals, 7 to 10% in persons who inject drugs, and 9 to 17% in men who have sex with men (MSM).[5] Impact of HIV on Natural History of HBV When compared to individuals with HBV monoinfection, those with HBV and HIV coinfection have higher baseline HBV DNA levels, lower alanine aminotransferase (ALT) levels, and decreased rates of spontaneous hepatitis B e antigen (HBeAg) seroconversion.[6] Individuals with HBV and HIV coinfection have an accelerated progression of liver disease, as well as an increased risk of hepatocellular carcinoma, all-cause mortality, and liver-related mortality compared to persons with HIV monoinfection (Figure 3).[7,8,9,10,11] In one study, investigators reported greater liver-related mortality in persons with HIV and HBV coinfection (14.2 per 1,000 person-years) than observed in either HIV monoinfection (1.7 per 1000 person-years) or HBV monoinfection (0.8 per 1,000 person-years).[12] Among those with HIV-HBV coinfection, the highest liver- related mortality rates have occurred in individuals with low CD4 cell counts.[13] Impact of HBV on Natural History of HIV Analysis of data from three different time periods of the Multicenter AIDS Cohort Study (MACS) study noted a higher liver-related mortality in persons with HIV-HBV coinfection than with HIV and hepatitis C virus (HCV) coinfection (Figure 4).[13] Multiple other studies have reported HIV-HBV coinfection and HIV-HCV coinfection both have played a major role in liver-related deaths in persons with HIV.[14,15,16,17,18,19] The impact of HBV on HIV natural history remains less clear, with some studies demonstrating no significant effect of HBV coinfection on HIV-related outcomes and others suggesting an adverse impact.[20,21,22] A recent large Page 1/46 observational cohort study from the United Kingdom reported higher all-cause mortality and liver-related mortality in persons with HIV if they had coinfection with HBV and/or HCV coinfection, but no increase in AIDS- related mortality (Figure 5).[23] Immunization to Prevent Hepatitis B Infection Although HBV vaccination has been recommended since the 1980s for men who have sex with men (as well as for persons who inject drugs and for heterosexuals with multiple sex partners), and since 2006 for all individuals with HIV, HBV vaccination rates for persons with HIV remain low.[4,24,25,26] Indeed, recent surveillance data from the Centers for Disease Control and Prevention (CDC) suggest that over a third of the persons living with HIV who were receiving medical care in the United States did not have documentation of HBV infection, immunity, or vaccination.[27] Recommendations and vaccine schedules for HBV are addressed in detail in the Immunizations in Adults Topic Review in the Basic Primary Care Module. Page 2/46 Screening for HBV in Persons with HIV Recommendations for Testing All persons with HIV should undergo initial screening for HBV infection upon entry into medical care with a panel that consists of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), and hepatitis B core antibody (anti-HBc total).[2] Chronic HBV infection is defined by the detection of HBsAg on two separate tests that have been obtained at least 6 months apart.[2] Thus, for persons who test positive for HBsAg, a repeat HBsAg test should be performed 6 months following this initial positive HBsAg to confirm that chronic HBV infection is present. Individuals with confirmed chronic HBV should have further testing that includes hepatitis B e antigen (HBeAg), antibody to HBeAg (anti-HBe), and HBV DNA.[2] In addition, for persons with HIV who have negative HBsAg testing, HBV DNA testing should be considered if they have persistent elevation in alanine aminotransferase levels (ALT) or they have suspected acute HBV infection and are in the serologic window period (loss of HBsAg without emergence yet of HBsAb).[28] Interpretation of Hepatitis B Serologic Studies Serologic testing for the diagnosis of HBV infection involves measurement of the full panel of distinct HBV- specific antigens and antibodies outlined above. Results of this serologic panel can help determine whether a patient is susceptible to infection, immune as a result of resolved infection, immune as a result of vaccination, acutely infected, or chronically infected (Figure 6).[26,29] Laboratory Markers Following Acute HBV Infection In persons with acute HBV infection, HBsAg can be detected in serum 4 to 10 weeks after HBV acquisition.[30] Although HBV DNA is usually detectable 10 to 20 days before the appearance of HBsAg, testing for HBV DNA is not part of routine HBV screening. Shortly after the appearance of HBsAg, HBeAg becomes evident; HBeAg is a marker of active viral replication and persons with positive HBeAg typically have high levels of circulating serum HBV DNA.[31] Concurrent with the onset of clinical symptoms, anti-HBc appears, primarily detectable as the IgM class (IgM anti-HBc). Although IgM anti-HBc antibodies typically decline to undetectable levels within 6 months, the IgG class (IgG anti-HBc) persists indefinitely as a marker of past HBV infection. Resolution of infection is marked by the loss of HBsAg and the appearance of HBsAb. Individuals who clear HBV infection will also lose HBeAg and develop anti-HBe. Isolated Hepatitis B Core Antibody Among persons with HIV who undergo serologic testing for HBV, an estimated 17 to 41% have isolated anti- HBc.[32,33] There are four possible interpretations of this finding: (1) resolved HBV infection with waning HBsAb titers (most common), (2) a false-positive anti-HBc test, (3) occult "low-level" chronic HBV infection, or (4) resolving acute HBV infection.[29] For persons with HIV and isolated anti-HBc, the Adult and Adolescent Opportunistic Infection Guidelines recommend the following approach (Figure 7).[2] This approach is based on finding from the NRS HB EP03 CISOVAC Prospective Study.[34,35] Administer a one-time dose of hepatitis B vaccine and check anti-HBs 1 to 2 months later. If the anti-HBs titer is greater than 100 IU/mL, then no further vaccination is required. Note that the cut-off value of 100 IU/mL used in this setting is higher than the usual cut-off of 10 IU/mL to document immunity following routine immunization with hepatitis B vaccine. If the anti-HBs titer is less than 100 IU/mL, then a complete series of HBV vaccine (single-dose or double-dose) should be administered, followed by anti-HBs testing 1 to 2 months after completing the series. Page 3/46 Evaluating and Counseling Persons with HBV-HIV Coinfection Individuals with HIV who are also diagnosed with chronic HBV (positive HBsAg on two occasions at least 6 months apart) should undergo further HBV-related evaluation and receive counseling. Laboratory studies, particularly HBeAg, anti-HBe, and HBV DNA levels, can help determine the phase of the chronic HBV infection; these phases represent a dynamic interaction between HBV replication and the host immune response (Figure 8).[36] The following information summarizes key recommendations for the initial evaluation of persons diagnosed with HBV in the setting of HIV coinfection:[2] Baseline HBV DNA Level: A quantitative HBV DNA level, in conjunction with serum ALT, provides key information that can help determine whether the patient has immune active infection. In persons with HBV monoinfection, the baseline HBV DNA level has also been shown to predict subsequent risk for cirrhosis and liver cancer.[37,38] If the person with HIV is already receiving HIV antiretroviral therapy with agents that have activity against HBV (e.g. tenofovir alafenamide, tenofovir DF, emtricitabine, and lamivudine), the HBV DNA level may be undetectable. HBeAg and anti-HBe: Baseline testing should include HBeAg and anti-HBe. HBeAg status helps determine the stage (phase) of HBV infection; loss of HBeAg associated with anti-HBe seroconversion is an important benchmark of therapy. HBV Genotype and Baseline Resistance Assay: Routine baseline HBV genotyping and resistance testing are not recommended. Serologic Studies for Hepatitis A Virus (HAV) and HCV: (1) Assess for HCV coinfection with HCV antibody and (2) determine immunity to HAV with HAV antibody (IgG or total).